Endophytes Are Hidden Producers of Maytansine in Putterlickia Roots

Abstract

Several recent studies have lent evidence to the fact that certain so-called plant metabolites are actually biosynthesized by associated microorganisms. In this work, we show that the original source organism(s) responsible for the biosynthesis of the important anticancer and cytotoxic compound maytansine is the endophytic bacterial community harbored specifically within the roots of Putterlickia verrucosa and P. retrospinosa plants. Evaluation of the root endophytic community by chemical characterization of their fermentation products using HPLC-HRMS(n), along with a selective microbiological assay using the maytansine-sensitive type strain Hamigera avellanea revealed the endophytic production of maytansine. This was further confirmed by the presence of AHBA synthase genes in the root endophytic communities. Finally, MALDI-imaging-HRMS was used to demonstrate that maytansine produced by the endophytes is typically accumulated mainly in the root cortex of both plants. Our study, thus, reveals that maytansine is actually a biosynthetic product of root-associated endophytic microorganisms. The knowledge gained from this study provides fundamental insights on the biosynthesis of so-called plant metabolites by endophytes residing in distinct ecological niches.

Spatial chemo-profiling of hypericin and related phytochemicals in Hypericum species using MALDI-HRMS imaging

“…For example, we used a combination of high-performance liquid chromatography-high-resolution mass spectrometry and MALDI-HRMS imaging to reveal that specific potent endophytic bacteria harbored in Cannabis sativa L. plants use quorum quenching as a possible antivirulence strategy to disrupt the cell-to-cell quorum-sensing signals in the biosensor strain, Chromobacterium violaceum [33]. More recently, using a similar approach, we revealed that the potent anticancer and cytotoxic compound maytansine is biosynthesized by the root-associated endophytic microorganisms of Putterlickia plants and is then further localized, typically within the root cortex, for a variety of ecological functions [34].…”

Discovery of Anticancer Agents of Diverse Natural Origin

“…Following the approval of brentuximab vedotin mentioned above, a second antibody–drug conjugate (ADC) was approved recently, namely, ado-tratuzamab emtansine, which is based in part on the natural product maytansine, and used for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (5, 6, 13, 14). While initially reported as deriving from a plant, it appears that maytansine is actually of bacterial endophyte origin (15). There are a relatively large number of natural products and their derivatives (inclusive of ADCs) currently in clinical trials as potential new oncolytic agents (5, 6, 14), so further new drugs of this type from a taxonomically varied range of organisms should reach the market.…”

Predominately Uncultured Microbes as Sources of Bioactive Agents

“…This molecule would subsequently be taken up from the plant’s rhizosphere and modified to produce maytansine by transesterification. In recent excellent work by the Spiteller group, in a paper in 2014, working with a Putterlickia species (one of the first plants from which maytansine was isolated), demonstrated that microbes in the plant’s rhizosphere were the source of maytansine, without any plant involvement (Kusari et al, 2014). …”